Smad2 Preserves Corneal Stromal Homeostasis by Restraining Profibrotic Smad3/YAP/TEAD2 Transcriptional Program

Area of Science:

• Ophthalmology
• Cell Biology
• Developmental Biology

Background:

• Corneal transparency relies on quiescent neural crest-derived stromal cells and controlled extracellular matrix.
• Fibrotic scarring, a major cause of blindness, results from disrupted corneal homeostasis.
• Transforming growth factor-beta (TGF-β)/Smad3 signaling is implicated in corneal fibrogenesis, but Smad2's role is unclear.

Purpose of the Study:

• To elucidate the distinct roles of Smad2 and Smad3 in corneal fibrogenesis.
• To investigate the molecular mechanisms underlying Smad2-deficient corneal fibrosis.
• To evaluate verteporfin as a therapeutic agent for preventing corneal scarring.

Main Methods:

• Smad2 ablation in neural crest cells using Wnt1-Cre mice.
• Single-cell RNA sequencing and virtual knockout analysis.
• Biochemical assays to detect protein complex formation.
• Pharmacologic inhibition of YAP/TEAD interaction with verteporfin.

Main Results:

• Smad2 deficiency in neural crest cells led to spontaneous corneal opacification, hypercellularity, and fibrosis.
• Smad2-null corneas exhibited activation of a Smad3-Yes-associated protein (YAP)/TEAD2 transcriptional program.
• Smad2 loss increased Smad3 phosphorylation and the formation of a nuclear Smad3-YAP-TEAD2 complex, driving fibrotic gene expression.
• Verteporfin treatment reversed corneal fibrosis and restored transparency in Smad2-deficient mice.

Conclusions:

• Smad2 is crucial for balancing Smad3 activity and preventing corneal fibrotic signaling.
• A novel convergence of YAP/TEAD and TGF-β/Smad3 signaling drives corneal fibrosis.
• Targeting the Smad3-YAP/TEAD interaction with verteporfin is a promising strategy to prevent corneal scarring and blindness.